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*Smoking

(Stroke. 1995;26:1409-1414.)
© 1995 American Heart Association, Inc.

Articles

Cigarette Smoking Accelerates Carotid Artery Intimal Hyperplasia in a Dose-Dependent Manner

Presented at the 20th International Joint Conference on Stroke and Cerebral Circulation, Charleston, SC, February 9-11, 1995.

Pavel V. Petrik, MD; Hugh A. Gelabert, MD; Wesley S. Moore, MD; William Quinones-Baldrich, MD Michael M. Law, MD

From the Section of Vascular Surgery, University of California at Los Angeles School of Medicine.

Correspondence to Hugh A. Gelabert, MD, UCLA School of Medicine, 10833 Le Conte Ave, Los Angeles, CA 90024.


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowMaterials and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Background and Purpose Intimal hyperplasia is the single most important cause of early restenosis after carotid endarterectomy. Cigarette smoking is an independent risk factor associated with peripheral vascular disease and cerebrovascular accidents. We undertook a dose-response experiment to determine the effect of cigarette smoke on development of intimal hyperplasia in a rat carotid artery intimal injury model.

Methods Seventy-two rats were divided into six equal groups and underwent standardized balloon injury to the carotid artery. Each group received 0 (controls), 1, 2, 3, 6, or 8 cigarettes per day for 4 weeks. Resultant intimal hyperplasia was expressed as a percentage of original lumen replaced by intimal hyperplasia.

Results Percent intimal hyperplasia development (±SD) was as follows: controls (0 cigarettes per day), 17.7±13.2; 1 cigarette per day, 22.8±15.0; 2 cigarettes per day, 20.0±14.7; 3 cigarettes per day, 19.2±12.1; 6 cigarettes per day, 43.5±15.5; and 8 cigarettes per day, 36.7±9.8. Six and 8 cigarettes per day significantly increased the development of intimal hyperplasia after intimal injury (P<.01).

Conclusions High-dose cigarette smoke accelerates development of intimal hyperplasia and may pose a significant risk factor in developing carotid restenosis.


Key Words: carotid arteries • cigarette smoking • hyperplasia • rats


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMaterials and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Stroke is the third leading cause of death in the United States and is associated with a high rate of morbidity.1 There are approximately 500 000 new stroke victims in the United States each year, and in 200 000 of these cases death quickly follows. At any one time, approximately one million stroke victims are alive and disabled.2 Carotid endarterectomy provides a means of restoring blood flow to affected cerebral areas and reduces the incidence of subsequent stroke.3 4 As the number of carotid endarterectomies performed in this country increases, so does the diversity of opinion regarding all elements of the operation. Proponents of carotid endarterectomy have sought to identify means of reducing both early and late surgical morbidity to improve surgical outcome.

Among the surgical complications targeted by these efforts is the problem of recurrent carotid stenosis. Restenosis rates of greater than 50% diameter reduction vary from 4% to 22%.5 6 7 8 9 10 11 12 13 Because of this, noninvasive monitoring of the carotid artery at regular intervals postoperatively, with surgery for stenosis greater than 80%, has been recommended.10 The majority of recurrent stenoses remain asymptomatic, and in most series symptoms are limited to severe lesions. The lack of data on the natural history of severe stenosis and on the risk factors for stenosis development preclude an informed decision on the role of surveillance or surgery.

Numerous risk factors have been investigated for an association with restenosis, including age,10 14 15 sex,6 11 13 15 16 17 diabetes,6 10 and smoking,6 15 16 17 18 each with varying results. Smoking in particular has demonstrated mixed results. We investigated the dose-response effect of cigarette smoke on the development of intimal hyperplasia in a well-described animal model.


*    Materials and Methods
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 *Materials and Methods
down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Seventy-two (six groups of 12 each) Sprague-Dawley rats weighing 300 to 500 g were placed in a smoking apparatus (detailed below) and exposed to increasing amounts of cigarette smoke daily until doses of 1, 2, 3, 6, and 8 cigarettes per day were achieved. Animals received their target smoke dosing for 1 week and then underwent standardized balloon injury of the carotid artery intima.

Our technique for standardized arterial balloon injury involves unilateral dissection of the right common carotid artery and cannulation of the external carotid artery. A 2F Fogarty balloon catheter (American Edwards Labs) was inserted and passed proximally toward the aortic arch. The balloon was inflated to 2 atm (Namic Co, Angiographic System Division) and withdrawn to the carotid artery bifurcation, resulting in denudation of the endothelium. The procedure was repeated three times with 120° rotation of the catheter between passes. This technique has been shown to induce a reproducible injury and has been used extensively in our laboratory.

The animals were exposed to cigarette smoke in an apparatus designed at the University of Kentucky for small animal smoke dosing.19 20 Rats were placed into individual wire containers that restrained them such that only their snouts were exposed in the intake port of the container. Eight rats restrained in this manner were then placed onto the exhaust manifold of the smoke machine at a time (Fig 1Down). Puffing was simulated by placing a lighted standard reference research cigarette (R1F4 cigarettes, University of Kentucky Tobacco and Health Research Institute) into a holder and subjecting it to 1 second of vacuum at 1-minute intervals. Smoke was conducted to the exhaust port by means of Tygon tubing (Norton Performance Plastics). Excess smoke was evacuated from the exhaust manifold by a separate vacuum source. The system was tuned such that 10 "puffs" fully consumed one cigarette. Rats were allowed 10-minute rest periods between each cigarette. The animals were exposed to their target dose of cigarette smoke 5 days a week for 4 weeks.



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  		Figure 1. Diagram shows apparatus used for small animal smoke dosing. Note eight rats restrained in wire containers with snouts placed into individual exhaust ports. A lighted cigarette is present within the timed vacuum container.

The vessels were then harvested by injection of 10 mL of 1% glutaraldehyde into the aortic root at systemic pressure to provide in vivo fixation while anatomic dimensions were maintained. After several minutes the animals were killed, and the arterial specimens were placed in 10% buffered formaldehyde. Three serial cross sections through the midportion of each artery were stained with Verhoeff–van Gieson stain by a professional histology laboratory (VCA Clinical Lab, Los Angeles, Calif).

The slide-mounted arterial lesions were studied with the use of morphometric analysis to quantitate the size of the intimal hyperplastic lesion. Photomicrographs of the stained sections were taken at a power of x80. Using a digital desktop planimeter (Lasico Graphic Digitizers) that converts tracings made by a hand-held cursor into units of length and area, we calculated the absolute cross-sectional area occupied by the intimal hyperplasia lesion and the circumference of the internal elastic lamina (IEL). Using this measurement of the IEL, we calculated the radius of the vessel by the following mathematical formula: Circumference (IEL measurement)=2{pi}r; r=IEL/2{pi}. Substituting this value of r into the formula {pi}r2 allows for calculation of a normalized luminal area. The hyperplastic lesion was then expressed as a percentage of the luminal area, allowing comparison among vessels of differing caliber.

Animal care complied with the "Principles of Laboratory Animal Care" (formulated by the National Society for Medical Research) and the Guide for the Care and Use of Laboratory Animals (National Institutes of Health publication No. 86-23, revised 1985).

Statistical analysis of intimal hyperplasia percent differences between controls and smoke-exposure groups included ANOVA and Dunnett's comparison.


*    Results
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 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 *Results
down arrowDiscussion
 down arrowReferences
 
Four deaths occurred at the time of preinjury smoke exposure, and six animals died after initial arterial injury. These animals were replaced with similarly pretreated animals. During the 4-week course of postinjury smoking, the following deaths per group occurred: 4 controls, 1 one-cigarette-per-day animal, 3 two-cigarettes-per-day animals, 1 six-cigarettes-per-day animal, and 5 eight-cigarettes-per-day animals. Control animals and several smoking cohort deaths were secondary to carotid artery stripping as evidenced by listless behavior, poor appetite, and partial paralysis immediately after recovery from anesthesia. These animals failed to recover over a period of time and were killed. At the time of vessel harvesting, no wound infections or other surgical complications were noted.

The results of the planimetric intimal hyperplasia/IEL calculations are summarized in the TableDown. An index of 0.00% indicates no intimal hyperplasia; 100% would represent complete occlusion. No statistical differences were shown in intimal hyperplasia percentage ratios between controls and animals exposed to low-dose (1, 2, and 3 cigarettes per day) cigarette smoke (P>.05). Animals receiving high doses of cigarette smoke (6 or 8 cigarettes per day) had statistically increased intimal hyperplasia percentage ratios compared with controls (P<.01).


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  		Table 1. Effect of Cigarette Smoke on Intimal Hyperplasia in Rats

Fig 2Down shows a control artery with a large amount of intimal hyperplasia 4 weeks after a balloon catheter injury. Fig 3Down shows an arterial cross section 4 weeks after a similar balloon catheter endothelial denudation and low-dose (1, 2, or 3 cigarettes per day) smoke exposure. The most significant amounts of intimal hyperplasia were demonstrated in animals exposed to high-dose (6 or more cigarettes per day) smoke for 4 weeks after balloon catheter injury (Fig 4Down).



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  		Figure 2. Photomicrograph of control (untreated) rat carotid artery after balloon catheter injury. Note internal elastic lamina (IEL) demarcating vessel lumen with enclosed intimal hyperplasia (IH) lesion (Verhoeff–van Gieson stain; original magnification x80).



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  		Figure 3. Photomicrograph of artery exposed to low-dose (2 to 3 cigarettes per day) smoke for 4 weeks shows moderate increase in degree of intimal hyperplasia (IH) (Verhoeff–van Gieson stain; original magnification x80). IEL indicates internal elastic lamina.



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  		Figure 4. Photomicrograph shows marked increase in development of intimal hyperplasia (IH) after exposure to high-dose (3 to 6 cigarettes per day) smoke for 4 weeks (Verhoeff–van Gieson stain; original magnification x80). IEL indicates internal elastic lamina.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 up arrowResults
 *Discussion
down arrowReferences
 
Recurrent arterial stenosis, first reported in the carotid artery by Stoney and String in 1976,21 had been recognized years earlier as contributing to vascular reconstructive failures.22 23 Numerous studies suggest that the majority of stenoses are fibroproliferative lesions of intimal hyperplasia that develop within 2 years of surgery and are asymptomatic when discovered.6 11 12 13 16 17 24 25 26 27 Studies following up patients after carotid endarterectomy with serial duplex ultrasound of the carotid artery demonstrate variable rates of restenosis; a greater than 50% diameter reduction was demonstrated in 4% to 22% of patients,5 6 7 8 9 10 11 12 13 and Park et al7 demonstrated 50% to 75% stenosis in 8.5% of patients and greater than 80% stenosis in 4% of patients followed up for a mean of 47 months after carotid endarterectomy. Although controversy exists as to the indications for reoperation, most clinicians currently recommend reoperation for symptomatic patients or those with greater than 80% stenosis.10

As a result of the frequency of restenosis after carotid endarterectomy and the morbidity associated with reoperation, many investigators have searched for risk factors associated with restenosis. Numerous patient-dependent characteristics have been investigated for association with an increased incidence of restenosis, including age,10 14 15 sex,6 11 13 15 16 17 diabetes,6 10 and smoking,6 15 16 17 18 each with varying results. Smoking, in particular, has demonstrated mixed results. Clagett et al15 and Reilly et al18 showed an increased incidence of restenosis in smokers, whereas Atnip et al,6 Ouriel and Green,17 and Thomas et al16 found no such relationship. We have demonstrated that exposure to high-dose cigarette smoke increases development of intimal hyperplasia in the injured carotid artery.

Previous clinical studies on the relationship between smoking and restenosis rates after carotid endarterectomy have been hampered by problems with sample size and accuracy of data on smoking habits. In addition, since most studies involve analysis of multiple factors, attempts at univariate analysis may not represent the true effect of cigarette smoke alone. Our study used equal numbers in each cohort group and in controls to ensure uniformity of effect among all groups studied. We also analyzed the dose-response effect of cigarette smoke on the development of intimal hyperplasia using a standard animal model to allow for study of a single variable in a controlled environment. Although control animals were not restrained in a manner similar to that of smoke-exposed animals during the course of the experiment, previous work in our laboratory demonstrated no significant differences in intimal hyperplasia development between restrained and unrestrained control animals (M.M.L, unpublished data, 1994).

The animals used in this study develop lesions after endothelial denudation similar to those found in areas of human intimal hyperplasia. This model has been used extensively by our laboratory and other investigators28 29 30 31 32 33 34 35 36 37 in studies of intimal hyperplasia. Although there are differences between the rat balloon catheter injury model compared with human restenosis after carotid endarterectomy, both processes involve the development of intimal hyperplasia. This process is usually attenuated in rats after 6 weeks but continues unabated in human lesions. Our model harvests the carotid artery 4 weeks after intimal injury to obtain hyperplastic lesions during the active proliferation phase (similar to that found in humans after intimal injury). Damage to the endothelium and media is a prominent feature in this model, as it is in human arteries after carotid endarterectomy, balloon angioplasty, atherectomy, and vein grafting. These lesions consist of a thickened intima with abundant smooth muscle cells and matrix (collagen, elastin, and proteoglycans); human lesions display prolific matrix but relatively fewer smooth muscle cells.23 38 39 40 41 42 43 44 45 46 Endothelial denudation is followed by platelet adherence to the exposed thrombogenic subendothelium. Platelets then spread and release vasoactive and thrombogenic factors, as well as growth factors (platelet-derived growth factor, transforming growth factor-ß, and epidermal growth factor).47 These factors are mitogenic for smooth muscle ingrowth and matrix deposition, with resultant intimal hyperplasia formation.

We have demonstrated a statistically significant increase in the development of intimal hyperplasia in the common carotid artery after exposure to smoke from 6 or 8 cigarettes per day. Animals exposed to 3 or fewer cigarettes per day failed to demonstrate a significant increase in intimal hyperplasia development. This suggests a threshold level at which the stimulatory effect of cigarette smoke is expressed. This effect of high-dose cigarette smoke may be secondary to alterations in platelet, endothelial cell, neutrophil, or smooth muscle cell functions or a combination thereof. Many studies have demonstrated an increase in the number of platelets or their activity after exposure to cigarette smoke.48 49 50 51 52 Rangemark et al51 showed an increase in both platelet number and in platelet/vessel wall interaction with smoke exposure. These effects were not seen with exposure to nicotine alone,49 and no sex differences were noted.51 In addition to an increased ability to aggregate, smoke also affects platelet biochemistry. Smith et al53 54 demonstrated inhibition of platelet mitochondrial activity after exposure to cigarette smoke. Although smokers demonstrate chronic activation of their platelets,50 the effect is reversible.50 52

Endothelial cells are also affected by exposure to cigarette smoke and may be responsible for the threshold effect seen with high-dose exposure. Injury to the endothelium from smoking disrupts normal regulatory properties and results in abnormal endothelial cell function.55 Endothelial cell wall permeability is increased, as is the likelihood of detachment with injury.56 In addition, smokers demonstrate decreased endothelial cell DNA synthesis.57 Similar to the reversible effects of cigarette smoke on platelets, endothelial dysfunction in smokers also does not appear to be permanent.58 Although our model uses denudation of endothelium to stimulate development of intimal hyperplasia, exposure to cigarette smoke before injury may potentiate the posttraumatic reaction of platelet and neutrophil stimulation and smooth muscle cell recruitment. In some models of atherosclerosis, for instance, endothelial cell dysfunction in smokers was shown before anatomic evidence of plaque formation was seen.59

Neutrophils are responsible for the release of vasoactive and mitogenic factors after injury and are integral to the development of intimal hyperplasia after endothelial injury. Smokers demonstrate alterations in neutrophil function at both the cellular and molecular levels.49 56 60 61 62 63 64 65 Cigarette smoke increases white blood cell counts49 and increases the activation of neutrophils by the complement system.65 Chemotactic functions of neutrophils are affected by smoke exposure,62 as is the production,60 composition,56 61 63 64 and release60 of neutrophil granules. Because of the importance of neutrophils in the initial stages of intimal hyperplasia development, any alterations in function secondary to cigarette smoke would likely affect vessel restenosis after injury.

Smooth muscle cell proliferation with associated extracellular matrix deposition results in the development of the intimal hyperplasia lesions actually responsible for luminal obstruction. Although the increased smooth muscle cell proliferation found in smokers may be secondary to endothelial and neutrophil dysfunction, there is also evidence that cigarette smoke itself may be responsible.55 66 67 68 Higman et al66 demonstrated smooth muscle cell proliferation, increased vasomotor tone, and impaired endothelium-derived relaxation from endothelium-derived relaxing factor in cigarette smokers. He67 found increased smooth muscle cell proliferation and migration to the intima of arteries after smoke exposure with a concomitant increase in extracellular matrix production. Polycyclic aromatic hydrocarbons in cigarette smoke, often implicated in the development of atherogenesis, have also been shown to increase smooth muscle cell proliferation and viability.68

The primary purpose of our study was to demonstrate the clinical effect of cigarette smoke on intimal hyperplasia. We did not seek to actually isolate the particular component(s) responsible for this effect. We hypothesize that exposure to carbon monoxide may play a role in the augmentation of intimal hyperplasia development after endothelial injury. Preliminary studies in this laboratory (P.V.P. et al, unpublished data, 1994) have demonstrated dose-responsive elevations in carbon monoxide and hemoglobin in rats exposed to cigarette smoke in an identical apparatus. Further immunohistochemical analysis with the use of monoclonal antibodies is currently under way to isolate the component(s) of intimal hyperplasia affected by cigarette smoke.

We conclude that high-dose cigarette smoke accelerates development of intimal hyperplasia in the injured rat carotid artery. Because of the similar intimal hyperplasia response in human carotid arteries after endothelial damage, smoking likely represents a significant risk factor in developing carotid restenosis and stroke. This effect was not demonstrated with low-dose exposure to cigarette smoke.


*    Acknowledgments
 
This study was supported in part by a grant from the Joash Foundation and the Veterans Administration merit review No. 911-040. We would like to thank Ted Henderson for performing the planimetry measurements and for his assistance with the care and preparation of animal subjects.

Received December 20, 1994; revision received March 17, 1995; accepted April 26, 1995.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 up arrowResults
 up arrowDiscussion
 *References
 

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